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Isoflurane and Propofol Inhibit Voltage-Gated Sodium Channels in Isolated Rat Neurohypophysial Nerve Terminals

Departments of Anesthesiology (W.O., H.C.H.), Neurology and Neuroscience (G.W.), and Pharmacology (H.C.H.), Weill Medical College of Cornell University, New York, New York

Mounting electrophysiological evidence indicates that certain general anesthetics, volatile anesthetics in particular, depress excitatory synaptic transmission by presynaptic mechanisms. We studied the effects of representative general anesthetics on voltage-gated Na⁺ currents (I_Na) in nerve terminals isolated from rat neurohypophysis using patch-clamp electrophysiological analysis. Both isoflurane and propofol inhibited I_Na in a dose-dependent and reversible manner. At holding potentials of -70 or -90 mV, isoflurane inhibited peak I_Na with IC₅₀ values of 0.45 and 0.56 mM, and propofol inhibited peak I_Na with IC₅₀ values of 4.1 and 6.0 µM, respectively. Isoflurane (0.8 mM) did not significantly alter the V_1/2 of activation; propofol caused a small positive shift. Isoflurane (0.8 mM) or propofol (5 µM) produced a negative shift in the voltage dependence of inactivation. Recovery of I_Na from inactivation was slower from a holding potential of -70 mV than from -90 mV; isoflurane and propofol further delayed recovery from inactivation. In conclusion, the volatile anesthetic isoflurane and the intravenous anesthetic propofol inhibit voltage-gated Na⁺ currents in isolated neurohypophysial nerve terminals in a concentration- and voltage-dependent manner. Marked effects on the voltage dependence and kinetics of inactivation and minimal effects on activation support preferential anesthetic interactions with the fast inactivated state of the Na⁺ channel. These results are consistent with direct inhibition of oxytocin and vasopressin release from the neurohypophysis by isoflurane and propofol. Inhibition of voltage-gated Na⁺ channels may contribute to the presynaptic effects of general anesthetics on nerve terminal excitability and neurotransmitter release.

Address correspondence to: Dr. Hugh C Hemmings, Jr., Department of Anesthesiology, Box 50, LC-203, 525 E. 68th St., Weill Medical College of Cornell University, New York, NY 10021. E-mail: hchemmi{at}med.cornell.edu

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